| Definition | | | | of PTH-rP 7. Increased PTH-rP production leads to |
| Parathyroid hormone (PTH) is secreted by the | | | | increased osteoclast formation and bone resorption, |
| parathyroid glands as a polypeptide containing 84 | | | | which in turn leads to increased amounts of active |
| amino acids. | | | | TGF-b, which subsequently lead to increased amounts |
| Related Peptide | | | | of PTH-rP expression by the breast cancer cells. |
| Parathyroid hormone–related peptide (PTHrP), a | | | | Indirect Effects of Parathyroid Hormone on Calcium: |
| peptide hormone derived from normal and tumor cells | | | | Parathyroid hormone also affects the metabolism of |
| that regulates bone metabolism and vascular tone, is | | | | inorganic phosphorus and probablyof magnesium, and |
| a naturally occurring angiogenesis inhibitor. | | | | in this way produces secondaryeffects on calcium. |
| Discovery | | | | The hormone inhibitsrenal tubular reabsorption of |
| In 1925, Collip prepared hot hydrochloric acid extracts | | | | inorganic phosphorusby a direct action on the renal |
| of the parathyroid glands, an approach which he | | | | tubules,resulting in an increase in urinary phosphorus |
| correctly deduced was needed to free the active | | | | and a fall of serum levels. The decrease in serum |
| substance from other gland stromal components and | | | | levels of inorganic phosphorus tends to raise the level |
| render it soluble. The author showed that these acid | | | | of calcium in the serum, by preventing precipitation of |
| extracts of the parathyroid gland would completely | | | | calcium phosphate in bone which occurs when the |
| relieve the tetany that followed parathyroidectomy, | | | | solubility product for calcium and phosphate is |
| and established the parathyroids as an endocrine | | | | exceeded 8. It has been shown that in the rat, |
| gland which secreted hormone (PTH) 1. | | | | parathyroid hormone also influences transport of |
| PTHrP was discovered in association with certain | | | | magnesium. Both parathyroid extract and pure bovine |
| types of cancer that caused elevated blood Ca2+ | | | | parathyroid hormone produce a fall in excretion of |
| levels (a syndrome called humoral hypercalcemia of | | | | magnesium in the urine, while parathyroidectomy |
| malignancy, or HHM) in affected patients 2. | | | | leads to a decrease in serum levels of magnesium 9. |
| Structural Characteristics | | | | These workers suggest that a fall in serum level of |
| The teleost PTH and PTHrP amino acid sequences | | | | magnesium stimulates the parathyroid glands, and the |
| contain a hydrophobic presequence and a putative | | | | increased secretion of hormone is the cause of the |
| prosequence, indicating that these are secreted | | | | hypercalcaemia which occurs in magnesium-deficient |
| peptides. The predicted mature zPTH1 and zPTH2 are | | | | rats. Changes in concentration of magnesium may |
| 68 and 67 amino acids long, respectively3, whereas | | | | therefore upset the normal homeostatic control of |
| the corresponding pufferfish pPTHA and pPTHB | | | | calcium. |
| mature peptides are 80 and 62 amino acids, | | | | References |
| respectively4. Among the fish, human, or chicken | | | | 1. Collip JB (1925). The extraction of a |
| mature PTHs, the amino acid identity is roughly | | | | parathyroid hormone which will prevent or control |
| 20–25%, although the sequence similarity is close | | | | parathyroid tetany and which regulates the level of |
| to 40%. However, there is high sequence | | | | blood calcium. J Biol Chem., 63:395-438. |
| conservation of the first 34 NH2-terminal amino acid | | | | 2. Moseley JM, Kubota M, Diefenbach-Jagger H, |
| residues, and 10 residues are either identical or have | | | | Wettenhall RE, Kemp BE, Suva LJ, Rodda CP, Ebeling |
| undergone conservative substitutions across all | | | | PR, Hudson PJ, Zajac JD, and Martin TJ (1987). |
| PTHs4. Among the conserved residues in the fish | | | | Parathyroid hormone-related protein purified from a |
| PTHs, several are critical for receptor binding and | | | | human lung cancer cell line. PNAS., 84:5048-5052. |
| signal transduction 3, 4. | | | | 3. Gensure RC, Ponugoti B, Gunes Y, Papasani |
| Mode of Action | | | | MR, Lanske B, Bastepe M, Rubin DA, Juppner H |
| Parathyroid hormone receptors are G protein-coupled | | | | (2004). Identification and characterization of two |
| members of the secretin receptor family that | | | | parathyroid hormone-like molecules in zebrafish. |
| interact with the NH2-terminal 34 amino acids of both | | | | Endocrinology, 145:1634-1639. |
| PTH and PTHrP (PTH1R) or PTH only (PTH2R). The | | | | 4. Canario AVM, Rotllant J, Fuentes J, Guerreiro |
| fact that the COOH-terminal regions of PTH and | | | | PM, Rita Teodosio H, Power DM, Clark MS (2006). |
| PTHrP have distinct functions from those mediated | | | | Novel bioactive parathyroid hormone and related |
| by the known PTH receptors suggests that other | | | | peptides in teleost fish. FEBS Lett., 580:291–299. |
| receptors may exist for these fragments 3. PTH and | | | | 5. Juppner H (1999).Receptors for parathyroid |
| PTHrP bind mammalian PTH1R with indistinguishable | | | | hormone and parathyroid hormone-related peptide: |
| affinity, and both ligands stimulate adenosine 3', | | | | exploration of their biological importance. Bone, |
| 5'-cyclic monophosphate (cAMP) and inositol | | | | 25:87-90. |
| 1,4,5-trisphosphate (IP3) accumulation with equivalent | | | | 6. Powell GJ, Southby J, Danks JA, Stillwell RG, |
| efficacy 5. | | | | Hayman JA, Henderson MA, Bennett RC & |
| Functions | | | | Martin TJ (1991). Localization of parathyroid |
| PTH-rP and osteolytic bone disease (or predominantly | | | | hormone-related protein in breast cancer metastases |
| osteolytic bone disease): Clinical studies have shown | | | | - increased incidence in bone compared with other |
| that breast cancer cells produce increased amounts | | | | sites. Can Res., 51:3059-3061. |
| of PTH-rP when they are present in the bone | | | | 7. Yin JJ, Chirgwin JM, Taylor SD, Dallas M, |
| microenvironment6. One of the major mechanisms by | | | | Massague J, Mundy GR & Guise TA (1996). |
| which this may occur is by tumor cell production of | | | | Dominant negative blockade of the transforming |
| PTH-rP in bone. This possibly occurs as a | | | | growth factor b (TGFb) type II receptordecreases |
| consequence of the release of TGF- ß ?by | | | | breast cancer-mediated osteolysis. Journal of Bone |
| resorbing bone, which enhances PTH-rP production by | | | | and Mineral Researc, 11:180. |
| breast cancer cells. It has been found that by | | | | 8. Harrison MT (1964). Interrelationships of |
| rendering human breast cancer cells unresponsive to | | | | vitamin D and parathyroid hormone in calcium |
| TGF- ß ?by stable transfection with a dominant | | | | homeostasis. Postgrad. Med. J., 40:497-505. |
| negative TGF- ß receptor, the tumor cells form | | | | 9. Boss M (1963). Parathyroid Hormone and |
| less bone metastases and secrete reduced amounts | | | | Magnesium Homceo- stasis. Nature, 198:1058. |